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词条 Orphenadrine
释义

  1. Medical use

  2. Side effects

  3. Pharmacology

  4. History

  5. Formulation

  6. Chemistry

      Stereochemistry  

  7. References

  8. External links

{{Drugbox
| verifiedrevid = 462265971
| IUPAC_name = (RS)-N,N-Dimethyl-2-[(2-methylphenyl)-phenyl-methoxy]-ethanamine
| image = Orphenadrine.svg
| tradename = Generic; many brand names worldwide[1]
| Drugs.com = {{drugs.com|monograph|norflex}}
| MedlinePlus = a682162
| pregnancy_AU = B2
| pregnancy_US = C
| legal_AU = S4
| legal_CA = OTC
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = Oral, intravenous, intramuscular
| bioavailability = 90%
| protein_bound = 95%
| metabolism = Hepatic demethylation
| elimination_half-life = 13-20 hours[1]
| excretion = Renal and biliary
| IUPHAR_ligand = 7251
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 83-98-7
| ATC_prefix = M03
| ATC_suffix = BC01
| ATC_supplemental = {{ATC|N04|AB02}}
| PubChem = 4601
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01173
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4440
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = AL805O9OG9
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08305
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 7789
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 900
| C=18 | H=23 | N=1 | O=1
| smiles = O(CCN(C)C)C(c1ccccc1)c2ccccc2C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C18H23NO/c1-15-9-7-8-12-17(15)18(20-14-13-19(2)3)16-10-5-4-6-11-16/h4-12,18H,13-14H2,1-3H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = QVYRGXJJSLMXQH-UHFFFAOYSA-N
}}

Orphenadrine (Norflex but also sold under many brand names worldwide[2]) is an anticholinergic drug of the ethanolamine antihistamine class; it is closely related to diphenhydramine. It is used to treat muscle pain and to help with motor control in Parkinson's disease, but has largely been superseded by newer drugs. It was discovered and developed in the 1940s.

As of 2015, the cost for a typical month of medication in the United States is US$25 to 50.[3]

Medical use

Orphenadrine is used to relieve pain caused by muscle injuries like strains and sprains in combination with rest and physical therapy.[4] A 2004 review found fair evidence that orphenadrine is effective for acute back or neck pain, but found insufficient evidence to establish the relative efficacy of the drug in relation to other drugs in the study.[5]

Orphenadrine and other muscle relaxants are sometimes used to treat pain arising from rheumatoid arthritis but there is no evidence they are effective for that purpose.[6]

A 2003 Cochrane Review of the use of anticholinergic drugs to improve motor function in Parkinson's disease found that as a class, the drugs are useful for that purpose; it identified one single-site randomised, cross-over study of orphenadrine vs placebo.[7] Orphenadrine and other anticholinergics have largely been superseded by other drugs; they have a use in alleviating motor function symptoms, and appear to help about 20% of people with Parkinson's.[9]

Side effects

Orphenadrine has the side effects of the other common antihistamines in large part. Stimulation is somewhat more common than with other related antihistamines, and is especially common in the elderly. Common side effects include dry mouth, dizziness, drowsiness, upset stomach or vomiting, constipation, urine retention, blurred vision, and headache.[4] Its use in Parkinson's is especially limited by these factors.[7]

People with glaucoma, digestive problems such as peptic ulcers or bowel obstruction, or sphincter relaxation disorders, or with enlarged prostate, bladder problems, or myasthenia gravis, should not take this drug.[8]

Pharmacology

Orphenadrine is known to have this pharmacology:

  • Nonselective mACh receptor antagonist (anticholinergic, 58% as potent as atropine)[9] Various monographs and package inserts, nursing manuals, journal articles and so forth have proposed the theory that this anticholinergic (atropine-like) activity, NMDA antagonism and possible local anaesthetic and miscellaneous analgesic effects may be the reason for orphenadrine's efficacy against muscle and other pain.[10] These reasons are behind the use of orphenadrine and other drugs of a number of types which are used with paracetamol, aspirin, naproxen, and similar agents with or without opioid analgesics to more effectively manage pain of various types.[11]
  • H1 receptor antagonist (antihistamine)[12]
  • NMDA receptor antagonist[13] (Ki-value of 6.0 +/- 0.7 μM, one third as potent as phencyclidine, which binds with a Ki of 2 μM)[14][15]
  • NET blocker (norepinephrine reuptake inhibitor)[16]
  • Nav1.7, Nav1.8, and Nav1.9 sodium channel blocker[17]
  • HERG potassium channel blocker[18]

History

George Rieveschl was a professor of chemistry at the University of Cincinnati and led a research program working on antihistamines. In 1943, one of his students, Fred Huber, synthesized diphenhydramine. Rieveschl worked with Parke-Davis to test the compound, and the company licensed the patent from him. In 1947 Parke-Davis hired him as their Director of Research. While he was there, he led the development of orphenadrine, an analog of diphenhydramine.[19]

Prior to the development of amantadine in the late 1960s and then other drugs, anticholinergics like orphenadrine were the mainstay of Parkinson's treatment.[20]

Formulation

Orphenadrine has been available as a citrate salt and a hydrochloride salt; in the US as of February 2016 the citrate form was available in tablets, extended release tablets, and by injection for acute use in a hospital setting.[2][21]

Orphenadrine is often available mixed with aspirin, paracetamol/acetaminophen, ibuprofen, caffeine, and/or codeine.[2]

Chemistry

Orphenadrine is a derivative of diphenhydramine with a methyl group added to one of the phenyl rings.[22]

Tofenacin is the N-desmethyl analogue of orphenadrine and an antidepressant.

Nefopam is a cyclized analogue of orphenadrine and diphenhydramine, with each different from one another only by the presence of one or two carbons.[23][24][25] It is used as an analgesic.

Stereochemistry

Orphenadrine has a chiral center and two enantiomers. Medictions are racemates.[26]

Enantiomers

(R)-orphenadrine
CAS number: 33425-91-1
(S)-orphenadrine
CAS number: 33425-89-7

References

1. ^{{cite journal|pmid=7056281|year=1982|last1=Labout|first1=JJ|last2=Thijssen|first2=C|last3=Keijser|first3=GG|last4=Hespe|first4=W|title=Difference between single and multiple dose pharmacokinetics of orphenadrine hydrochloride in man|volume=21|issue=4|pages=343–50|journal=European Journal of Clinical Pharmacology|doi=10.1007/BF00637624}}
2. ^1 2 3 [https://www.drugs.com/international/orphenadrine.html Drugs.com international listings for orphenadrine] Page accessed Feb 5, 2016
3. ^{{cite book|last1=Hamilton|first1=Richart|title=Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition|date=2015|publisher=Jones & Bartlett Learning|isbn=9781284057560|page=2}}
4. ^1 Medline Plus. [https://www.nlm.nih.gov/medlineplus/druginfo/meds/a682162.html Medline Plus entry for Orphenadrine]. Page last updated December 1, 2010. Page accessed February 6, 2016]
5. ^Chou R, Peterson K, Helfand M. Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage. 2004 Aug;28(2):140-75. {{PMID|15276195}}
6. ^Richards BL, Whittle SL, Buchbinder R. Muscle relaxants for pain management in rheumatoid arthritis. Cochrane Database Syst Rev. 2012 Jan 18;1:CD008922. {{PMID|22258993}}
7. ^1 Katzenschlager R, et al. Anticholinergics for symptomatic management of Parkinson's disease. Cochrane Database Syst Rev. 2003;(2):CD003735. {{PMID|12804486}}
8. ^Orphenadrine Citrate Extended release label Revised October 1998
9. ^{{cite journal |vauthors=Syvälahti EK, Kunelius R, Laurén L | title = Effects of antiparkinsonian drugs on muscarinic receptor binding in rat brain, heart and lung | journal = Pharmacology & Toxicology | volume = 62 | issue = 2 | pages = 90–4 |date=February 1988 | pmid = 3353357 | doi = 10.1111/j.1600-0773.1988.tb01852.x| url = }}
10. ^Nurses' Drug Guide 2010
11. ^{{cite journal |vauthors=Rumore MM, Schlichting DA | title = Analgesic effects of antihistaminics | journal = Life Sciences | volume = 36 | issue = 5 | pages = 403–16 |date=February 1985 | pmid = 2578597 | doi = 10.1016/0024-3205(85)90252-8| url = }}
12. ^{{cite journal |vauthors=Rumore MM, Schlichting DA | title = Analgesic effects of antihistaminics | journal = Life Sciences | volume = 36 | issue = 5 | pages = 403–16 |date=February 1985 | pmid = 2578597 | doi = 10.1016/0024-3205(85)90252-8| url = }}
13. ^{{cite journal | author = Kornhuber J | title = Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies | journal = Journal of Neural Transmission. General Section | volume = 102 | issue = 3 | pages = 237–46 | year = 1995 | pmid = 8788072 | doi = 10.1007/BF01281158| url = |name-list-format=vanc| author2 = Parsons CG | author3 = Hartmann S | display-authors = 3 | last4 = Retz | first4 = W. | last5 = Kamolz | first5 = S. | last6 = Thome | first6 = J. | last7 = Riederer | first7 = P. }}
14. ^{{Cite journal|title=Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies.|journal=Journal of Neural Transmission |author1=J Kornhuber |author2=C G Parsons |author3=S Hartmann |author4=W Retz |author5=S Kamolz |author6=J Thome |author7=P Riederer |pmid=8788072|doi=10.1007/BF01281158|volume=102|issue=3|year=1995|pages=237–46}}
15. ^{{Cite journal| title=NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia.| journal=Molecular Psychiatry| author=Kapur S1, Seeman P.| pmid=12232776 | doi=10.1038/sj.mp.4001093|volume=7|issue=8|year=2002|pages=837–44}}
16. ^{{cite journal | author = Pubill D | title = Assessment of the adrenergic effects of orphenadrine in rat vas deferens | journal = The Journal of Pharmacy and Pharmacology | volume = 51 | issue = 3 | pages = 307–12 |date=March 1999 | pmid = 10344632 | doi = 10.1211/0022357991772303| url = http://openurl.ingenta.com/content/nlm?genre=article&issn=0022-3573&volume=51&issue=3&spage=307&aulast=Pubill |name-list-format=vanc| author2 = Canudas AM | author3 = Pallàs M | display-authors = 3 | last4 = Sureda | first4 = F.X. | last5 = Escubedo | first5 = E. | last6 = Camins | first6 = A. | last7 = Camarasa | first7 = J.}}
17. ^{{cite journal | author = Desaphy JF | title = Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine | journal = Pain | volume = 142 | issue = 3 | pages = 225–35 |date=April 2009 | pmid = 19217209 | doi = 10.1016/j.pain.2009.01.010 | url = http://linkinghub.elsevier.com/retrieve/pii/S0304-3959(09)00039-6 |name-list-format=vanc| author2 = Dipalma A | author3 = De Bellis M | display-authors = 3 | last4 = Costanza | first4 = Teresa | last5 = Gaudioso | first5 = Christelle | last6 = Delmas | first6 = Patrick | last7 = George | first7 = Alfred L. | last8 = Camerino | first8 = Diana Conte}}
18. ^{{cite journal | author = Scholz EP | title = Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656 | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 376 | issue = 4 | pages = 275–84 |date=December 2007 | pmid = 17965852 | doi = 10.1007/s00210-007-0202-6 |name-list-format=vanc| author2 = Konrad FM | author3 = Weiss DL | display-authors = 3 | last4 = Zitron | first4 = Edgar | last5 = Kiesecker | first5 = Claudia | last6 = Bloehs | first6 = Ramona | last7 = Kulzer | first7 = Martin | last8 = Thomas | first8 = Dierk | last9 = Kathöfer | first9 = Sven}}
19. ^Walter Sneader. Drug Discovery: A History. John Wiley & Sons, 2005 {{ISBN|9780471899792}}. [https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA405 Page 405]
20. ^1 Ivan Donaldson, C. David Marsden, Susanne Schneider. Marsden's Book of Movement Disorders. Oxford University Press, 2012. {{ISBN|9780192619112}}. [https://books.google.com/books?id=g815isikVSAC&pg=PA281 Page 281]
21. ^FDA listing of Orphenadrine citrate registrations. Page accessed Feb 6, 2016
22. ^Christophe Morice and Camille Wermuth. Ring Transformations. Chapter 9 in The Practice of Medicinal Chemistry, 4th Edition. Eds. Camille Georges Wermuth, David Aldous, Pierre Raboisson, Didier Rognan. Elsevier, 2015 {{ISBN|9780124172135}} [https://books.google.com/books?id=dtScBAAAQBAJ&pg=PA251#v=onepage&q&f=false pp. 250-251]
23. ^{{cite book|author1=Camille Georges Wermuth|author2=David Aldous|author3=Pierre Raboisson|author4=Didier Rognan|title=The Practice of Medicinal Chemistry|url=https://books.google.com/books?id=dtScBAAAQBAJ&pg=PA250|date=1 July 2015|publisher=Elsevier Science|isbn=978-0-12-417213-5|pages=250–251}}
24. ^{{cite book|author=Walter Sneader|title=Drug Discovery: A History|url=https://books.google.com/books?id=Cb6BOkj9fK4C&pg=PA405|date=23 June 2005|publisher=John Wiley & Sons|isbn=978-0-471-89979-2|pages=405–}}
25. ^{{cite book|author1=Hugo Kubinyi|author2=Gerhard Müller|title=Chemogenomics in Drug Discovery: A Medicinal Chemistry Perspective|url=https://books.google.com/books?id=oxvYXJSCImUC&pg=PA54|date=6 March 2006|publisher=John Wiley & Sons|isbn=978-3-527-60402-9|pages=54–}}
26. ^Rote Liste Service GmbH (Hrsg.): Rote Liste 2017 – Arzneimittelverzeichnis für Deutschland (einschließlich EU-Zulassungen und bestimmter Medizinprodukte). Rote Liste Service GmbH, Frankfurt/Main, 2017, Aufl. 57, {{ISBN|978-3-946057-10-9}}, S. 207.

External links

  • {{MedlinePlusDrugInfo|medmaster|a682162}}
{{Muscle relaxants}}{{Analgesics}}{{Antiparkinson}}{{Navboxes
| title = Pharmacodynamics
| titlestyle = background:#ccccff
| list1 ={{Histamine receptor modulators}}{{Ion channel modulators}}{{Ionotropic glutamate receptor modulators}}{{Monoamine reuptake inhibitors}}{{Muscarinic acetylcholine receptor modulators}}
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9 : Amines|Ethers|H1 receptor antagonists|Muscarinic antagonists|Muscle relaxants|Norepinephrine reuptake inhibitors|NMDA receptor antagonists|Sodium channel blockers|Potassium channel blockers
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